content: <PAGE>   1
       As filed with the Securities and Exchange Commission on August 4, 2000
  
                                                             REGISTRATION NO. 333-
  ================================================================================
                  UNITED STATES SECURITIES AND EXCHANGE COMMISSION
                               Washington, D.C. 20549
                                 __________________
  
                                      FORM S-8
                            REGISTRATION STATEMENT UNDER
                             THE SECURITIES ACT OF 1933
                                 __________________
  
                                    ARQULE, INC.
               (Exact name of registrant as specified in its charter)
  
  <TABLE>
  <CAPTION>
  <S>                                                                          <C>
                  DELAWARE                                                                  04-3221586
  (State or other jurisdiction of incorporation)                               (I.R.S. Employer Identification No.)
  </TABLE>
  
                        19 PRESIDENTIAL WAY, WOBURN, MA 01801
                      (Address of Principal Executive Offices)
                                 __________________
  
                AMENDED AND RESTATED 1996 DIRECTOR STOCK OPTION PLAN
                              (Full Title of the Plan)
  
                                 DR. STEPHEN A. HILL
                        President and Chief Executive Officer
                                    ArQule, Inc.
                                 19 Presidential Way
                             Woburn, Massachusetts 01801
                                   (781) 994-0300
              (Name, address and telephone number of agent for service)
  
                                   with copies to:
                               MICHAEL E. LYTTON, ESQ.
                                 Palmer & Dodge LLP
                                  One Beacon Street
                             Boston, Massachusetts 02108
                                   (617) 573-0100
                                 __________________
                           CALCULATION OF REGISTRATION FEE
  
  <TABLE>
  <CAPTION>
  ---------------------------------------------------------------------------------------------------------------------
                                                            Proposed maximum      Proposed maximum
  Title of each class of securities      Amount to be      offering price per    aggregate offering       Amount of
           to be registered            registered (1)(2)          share                price          registration fee
  --------------------------------------------------------------------------------------------------------------------
  <S>                                  <C>                   <C>                   <C>                     <C>
  Common Stock, $0.01 par value          65,500 shares       $16.625(3)            $1,088,938(3)           $288
  =====================================================================================================================
  
  </TABLE>
  
  
  (1)  Pursuant to Rule 416 under the Securities Act of 1933, to the extent
       additional shares of our common stock may be issued or issuable as a result
       of a stock split or other distribution declared at any time by the Board of
       Directors while this registration statement is in effect, this registration
       statement is hereby deemed to cover all such additional shares common
       stock.
  (2)  This registration statement registers an additional 65,500 shares issuable
       under our Amended and Restated 1996 Director Stock Option Plan. We have
       previously registered 125,000 shares under this plan (File No. 333-25369).
  (3)  Estimated solely for the purpose of determining the registration fee and
       computed pursuant to Rule 457(h)(1). The proposed maximum offering price
       per share indicated equals the last per share sale price of ArQule common
       stock on August 1, 2000 as reported by the Nasdaq National Market.
  
  
  <PAGE>   2
  
  
                                       PART II
  
                 INFORMATION REQUIRED IN THE REGISTRATION STATEMENT
  
  
  STATEMENT REGARDING INCORPORATION OF INFORMATION BY REFERENCE FROM EFFECTIVE
  REGISTRATION STATEMENT
  
       Pursuant to Instruction E to Form S-8, the contents of our registration
  statement on Form S-8 filed with the Securities and Exchange Commission on April
  17, 1997 (File No. 333-25369) relating to the registration of 125,000 shares of
  our common stock authorized for issuance under the our Amended and Restated 1996
  Director Stock Option Plan is incorporated by reference in its entirety in this
  registration statement. This registration statement provides for the
  registration of an additional 65,500 shares of our common stock authorized for
  issuance under our Amended and Restated 1996 Director Stock Option Plan.
  
  ITEM 8
  
       See Exhibit Index immediately following the signature page.
  
  
  <PAGE>   3
  
  
                                     SIGNATURES
  
       Pursuant to the requirements of the Securities Act of 1933, the Registrant
  certifies that it has reasonable grounds to believe that it meets all of the
  requirements for filing on Form S-8 and has duly caused this Registration
  Statement to be signed on its behalf by the undersigned, thereunto duly
  authorized, in the City of Woburn, Commonwealth of Massachusetts, on this 4th
  day of August, 2000.
  
                                         ARQULE, INC.
  
  
                                         By: /s/ Stephen A. Hill
                                             -------------------------------------
                                             Stephen A. Hill
                                             President and Chief Executive Officer
  
  
                                  POWER OF ATTORNEY
  
           We, the undersigned officers and directors of ArQule, Inc., hereby
  severally constitute and appoint Stephen A. Hill, David C. Hastings, Michael E.
  Lytton and Lynnette C. Fallon, and each of them singly, our true and lawful
  attorneys-in-fact, with full power to them in any and all capacities, to sign
  any and all amendments to this Registration Statement on Form S-8 (including any
  post-effective amendments thereto), and to file the same, with exhibits thereto
  and other documents in connection therewith, with the Securities and Exchange
  Commission, hereby ratifying and confirming all that each of said
  attorneys-in-fact may do or cause to be done by virtue hereof.
  
           Pursuant to the requirements of the Securities Act of 1933, this
  Registration Statement has been signed below by the following persons in the
  capacities and on the dates indicated:
  
  <TABLE>
  <CAPTION>
               SIGNATURE                                       TITLE                              DATE
               ---------                                       -----                              ----
  
  <S>                                                 <C>                                    <C>
    /s/  Stephen A. Hill                              Principal Executive                    August 4, 2000
  ----------------------------------------            Officer and Director
  Stephen A. Hill
  
    /s/  David C. Hastings                            Principal Financial and                August 4, 2000
  ----------------------------------------            Accounting Officer
  David C. Hastings
  
    /s/  Laura Avakian                                Director                               August 4, 2000
  ----------------------------------------
  Laura Avakian
  
    /s/  Werner Cautreels                             Director                               August 4, 2000
  ----------------------------------------
  Werner Cautreels
  
    /s/  L. Patrick Gage                              Director                               August 4, 2000
  ----------------------------------------
  L. Patrick Gage
  
  ________________________________________            Director
  Tuan Ha-Ngoc
  
    /s/  Michael Rosenblatt                           Director                               August 4, 2000
  ----------------------------------------
  Michael Rosenblatt
  </TABLE>
  
  
  <PAGE>   4
  
  
                                    EXHIBIT INDEX
  
  
  <TABLE>
  <CAPTION>
        EXHIBIT NUMBER                                              DESCRIPTION
        --------------                                              -----------
  
  <S>                         <C>
             4.1              Amended and Restated By-laws of the Company. Filed as Exhibit 3.1 to the Company's
                              Quarterly Report on Form 10-Q for the quarter ended June 30, 1999 (file No. 000-21429)
                              and incorporated herein by reference.
  
              5               Opinion of Palmer & Dodge LLP. Filed herewith.
  
             23.1             Consent of PricewaterhouseCoopers LLP. Filed herewith.
  
             23.2             Consent of Palmer & Dodge LLP (contained in Exhibit 5).
  
             99.1             Amended and Restated 1996 Director Stock Option Plan. Filed as Appendix C to our
                              Proxy Statement on Schedule 14A filed on April 14, 2000 (File No. 000-21429) and
                              incorporated herein by reference.
  </TABLE>
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metadata_filer: {"company-data": {"conformed-name": "ARQULE INC", "cik": "0001019695", "assigned-sic": "2834", "irs-number": "043221586", "state-of-incorporation": "DE", "fiscal-year-end": "1231"}, "filing-values": {"form-type": "S-8", "act": "33", "file-number": "333-43046", "film-number": "686227"}, "business-address": {"street1": "200 BOSTON AVE", "city": "MEDFORD", "state": "MA", "zip": "02155", "phone": "6173954100"}, "mail-address": {"street1": "200 BOSTON AVE", "city": "MEDFORD", "state": "MA", "zip": "02155"}}
text: 1
       As filed with the Securities and Exchange Commission on August 4, 2000
  
                                                             REGISTRATION NO. 333-
  ================================================================================
                  UNITED STATES SECURITIES AND EXCHANGE COMMISSION
                               Washington, D.C. 20549
                                 __________________
  
                                      FORM S-8
                            REGISTRATION STATEMENT UNDER
                             THE SECURITIES ACT OF 1933
                                 __________________
  
                                    ARQULE, INC.
               (Exact name of registrant as specified in its charter)
  DELAWARE                                                                  04-3221586
  (State or other jurisdiction of incorporation)                               (I.R.S. Employer Identification No.)
  19 PRESIDENTIAL WAY, WOBURN, MA 01801
                      (Address of Principal Executive Offices)
                                 __________________
  
                AMENDED AND RESTATED 1996 DIRECTOR STOCK OPTION PLAN
                              (Full Title of the Plan)
  
                                 DR. STEPHEN A. HILL
                        President and Chief Executive Officer
                                    ArQule, Inc.
                                 19 Presidential Way
                             Woburn, Massachusetts 01801
                                   (781) 994-0300
              (Name, address and telephone number of agent for service)
  
                                   with copies to:
                               MICHAEL E. LYTTON, ESQ.
                                 Palmer & Dodge LLP
                                  One Beacon Street
                             Boston, Massachusetts 02108
                                   (617) 573-0100
                                 __________________
                           CALCULATION OF REGISTRATION FEE
  ---------------------------------------------------------------------------------------------------------------------
                                                            Proposed maximum      Proposed maximum
  Title of each class of securities      Amount to be      offering price per    aggregate offering       Amount of
           to be registered            registered (1)(2)          share                price          registration fee
  --------------------------------------------------------------------------------------------------------------------
  Common Stock, $0.01 par value          65,500 shares       $16.625(3)            $1,088,938(3)           $288
  =====================================================================================================================
  (1)  Pursuant to Rule 416 under the Securities Act of 1933, to the extent
       additional shares of our common stock may be issued or issuable as a result
       of a stock split or other distribution declared at any time by the Board of
       Directors while this registration statement is in effect, this registration
       statement is hereby deemed to cover all such additional shares common
       stock.
  (2)  This registration statement registers an additional 65,500 shares issuable
       under our Amended and Restated 1996 Director Stock Option Plan. We have
       previously registered 125,000 shares under this plan (File No. 333-25369).
  (3)  Estimated solely for the purpose of determining the registration fee and
       computed pursuant to Rule 457(h)(1). The proposed maximum offering price
       per share indicated equals the last per share sale price of ArQule common
       stock on August 1, 2000 as reported by the Nasdaq National Market.
  2
  
                                       PART II
  
                 INFORMATION REQUIRED IN THE REGISTRATION STATEMENT
  
  STATEMENT REGARDING INCORPORATION OF INFORMATION BY REFERENCE FROM EFFECTIVE
  REGISTRATION STATEMENT
  
       Pursuant to Instruction E to Form S-8, the contents of our registration
  statement on Form S-8 filed with the Securities and Exchange Commission on April
  17, 1997 (File No. 333-25369) relating to the registration of 125,000 shares of
  our common stock authorized for issuance under the our Amended and Restated 1996
  Director Stock Option Plan is incorporated by reference in its entirety in this
  registration statement. This registration statement provides for the
  registration of an additional 65,500 shares of our common stock authorized for
  issuance under our Amended and Restated 1996 Director Stock Option Plan.
  
  ITEM 8
  
       See Exhibit Index immediately following the signature page.
  3
  
                                     SIGNATURES
  
       Pursuant to the requirements of the Securities Act of 1933, the Registrant
  certifies that it has reasonable grounds to believe that it meets all of the
  requirements for filing on Form S-8 and has duly caused this Registration
  Statement to be signed on its behalf by the undersigned, thereunto duly
  authorized, in the City of Woburn, Commonwealth of Massachusetts, on this 4th
  day of August, 2000.
  
                                         ARQULE, INC.
  
                                         By: /s/ Stephen A. Hill
                                             -------------------------------------
                                             Stephen A. Hill
                                             President and Chief Executive Officer
  
                                  POWER OF ATTORNEY
  
           We, the undersigned officers and directors of ArQule, Inc., hereby
  severally constitute and appoint Stephen A. Hill, David C. Hastings, Michael E.
  Lytton and Lynnette C. Fallon, and each of them singly, our true and lawful
  attorneys-in-fact, with full power to them in any and all capacities, to sign
  any and all amendments to this Registration Statement on Form S-8 (including any
  post-effective amendments thereto), and to file the same, with exhibits thereto
  and other documents in connection therewith, with the Securities and Exchange
  Commission, hereby ratifying and confirming all that each of said
  attorneys-in-fact may do or cause to be done by virtue hereof.
  
           Pursuant to the requirements of the Securities Act of 1933, this
  Registration Statement has been signed below by the following persons in the
  capacities and on the dates indicated:
  SIGNATURE                                       TITLE                              DATE
               ---------                                       -----                              ----
  /s/  Stephen A. Hill                              Principal Executive                    August 4, 2000
  ----------------------------------------            Officer and Director
  Stephen A. Hill
  
    /s/  David C. Hastings                            Principal Financial and                August 4, 2000
  ----------------------------------------            Accounting Officer
  David C. Hastings
  
    /s/  Laura Avakian                                Director                               August 4, 2000
  ----------------------------------------
  Laura Avakian
  
    /s/  Werner Cautreels                             Director                               August 4, 2000
  ----------------------------------------
  Werner Cautreels
  
    /s/  L. Patrick Gage                              Director                               August 4, 2000
  ----------------------------------------
  L. Patrick Gage
  
  ________________________________________            Director
  Tuan Ha-Ngoc
  
    /s/  Michael Rosenblatt                           Director                               August 4, 2000
  ----------------------------------------
  Michael Rosenblatt
  4
  
                                    EXHIBIT INDEX
  EXHIBIT NUMBER                                              DESCRIPTION
        --------------                                              -----------
  4.1              Amended and Restated By-laws of the Company. Filed as Exhibit 3.1 to the Company's
                              Quarterly Report on Form 10-Q for the quarter ended June 30, 1999 (file No. 000-21429)
                              and incorporated herein by reference.
  
              5               Opinion of Palmer & Dodge LLP. Filed herewith.
  
             23.1             Consent of PricewaterhouseCoopers LLP. Filed herewith.
  
             23.2             Consent of Palmer & Dodge LLP (contained in Exhibit 5).
  
             99.1             Amended and Restated 1996 Director Stock Option Plan. Filed as Appendix C to our
                              Proxy Statement on Schedule 14A filed on April 14, 2000 (File No. 000-21429) and
                              incorporated herein by reference.